Some Straight Talk To CMOs

By Louis Garguilo, Chief Editor, Outsourced Pharma

Achaogen’s Tina Larson opens up on the real business needs of sponsors.

"I spent much of my career as an introverted engineer, only comfortable speaking to close colleagues and avoiding crowds," says Tina Larson, VP of technical operations at Achaogen. She may be indulging in a bit of introversion inflation. After all, her career included a successful climb through Genentech, starting as that shy associate engineer and then progressing to leadership roles, including global head of technical development in business operations (Roche), before she moved to Achaogen last year. (And does that look like an introvert on our cover?) In one of my recent conversations with Larson she says: “I used to be so cautious. Now it’s time to be more open and provocative.”

Fortunately, we get both sides of Larson as she explores the real needs of drug sponsors today. She offers up thoughts like this: “It’s interesting to think about why the small molecule industry, including CDMOs and CMOs, hasn’t learned or revolutionized in the way the biologics industry has, even in places where we have common technology.” And this: “If you can get 200 percent more out of a biologics manufacturing process from a CMO, who cares? That’s not what’s driving our business decisions.”

A Large Step Back, A Small Step Forward
At Achaogen, Larson is working on the global push for a repioneering of the antibiotics space. “By 2050,” she says, “antimicrobial resistance is projected to kill more people than cancer unless we do something. Our industry needs to revitalize its ability to bring novel antibiotics to market. And we need to do it now.”

She’s got her challenges. “Although I went from driving innovation in biologics manufacturing facilities to this cutting-edge work on next-generation antibiotics, still for me it’s like a journey back in time a few decades,” says Larson. That journey requires recalibrating herself to older, small molecule manufacturing facilities, after spending a career inside their younger biologic cousins. “I’ve recently seen technologies like something out of the early 1980s, for example in chromatography steps, which should be more in common to both facilities,” she says. “Biologics plants are just not that old.”

Nonetheless, Larson says it’s instructive to have this “back-in-time experience,” and enjoys the challenge of partnering with CMOs in her new space. “Engaging a small molecule service provider feels different from engaging a biologics CMO,” she explains. “I have to admit, my first questions were: ‘What motivation do small molecule CMOs have to modernize? Is this segment of our industry actually interested in modernizing drug manufacturing?’”

Larson isn’t impugning past models or motivations. Rather, she’s encouraged that with the renewed, worldwide, and urgent focus on antibiotics today, positive change is on the way. In fact, her experience, and that of others like her, may be just the medicine needed for advancement.

“I can see our future within those biologics plants I was used to previously,” she explains. “I bet a decade from now, we’ll visit today’s small molecule facilities, and perhaps with the help of professionals from cellbased therapy companies and others, they’ll be the ones driving innovation and the next generation of transformative technology. Small molecule manufacturing has the potential to be so much more elegant, because the chemistry is so well characterized compared to biologics. Manufacturers have just lacked the business drivers to modernize. I can see this changing.”

But there’s also a twist in her narrative, because she feels that the biologics facilities are starting to seem dated; it won’t be long before we are talking about how old these plants are. So where to look next? “The new kids on the block are smaller organizations using, for example, technologies for single-use solutions, enabling more potent, niche, and cell-based therapies,” she replies. “To enable new antibiotics, we need both small molecule and biologics manufacturers that are cost-effective, but most importantly, focused on speed to market.”

But more on the business needs of speed to market later. First, let’s quickly review the drug development and manufacturing environment where that speed must take place.

Depending On Disruption?
A lack of innovation speaks directly to institutionalized industry barriers. They include an elongated product-development cycle for new drugs, extended on-the-market timelines, and regulatory roadblocks. This list provides a partial answer to Larson’s question above of motivation: Both sponsors and service providers (perhaps particularly on the small molecule side) can, to a degree, get away without innovating and still achieve relative success.

A most obvious challenge to innovation lies with the filing of an NDA (new drug application) or BLA (biologic license application), setting off what’s become a regulatory process with immense impact on markets for drug owners. Says Larson, “The global nature of managing a supply chain and making postmarket or even premarket changes is so daunting and expensive you need an incredibly good reason to implement any innovations to process or manufacturing technologies.”

She notes that most plants are still designed to run drug substance and product processes without variation, and often for decades. Furthermore, when the next development drug is introduced into a facility — external or internal — the temptation is to try to fit even that potentially modernized process, in which you could implement innovation, into the existing equipment and technology in the plant. So not only do we have a problem innovating on products that are already commercially available, we have one innovating on products throughout the entire pipeline. “It becomes self-sustaining,” Larson laments. “The only way this gets altered is when you have something truly disruptive — like cellbased therapies — where you are forced to do things completely different.”

Waiting for these innovation disruptions can mean patients, pricing, and products are slow to benefit from any modernization. Nevertheless, Larson believes there are still incremental ways to modernize and innovate in the supply chain. “For example, I’ve had great experiences collaborating on process analytical technology [PAT] via crossindustry groups. I’ve also worked with these groups on technology-development road maps for biologics manufacturing. Cross-industry technical experts will come together for a mutual goal, and I witnessed the collaboration among users of emerging single-use technologies. There’s a big benefit to standardizing single- use equipment options, similar to the benefit we all get in our daily lives from using standard USB connectors for our communication devices. The fundamental question always has been: How can we together advance meaningful innovation into our industry, and learn to help the suppliers help us in the effort?”

A good place to start might be ensuring service providers understand the meaning of “meaningful” to their customers, which brings us back to speed to market and understanding real business drivers.

Change For The Good Or No Change At All
Unfortunately, says Larson, there can be a disconnect between drug developers and their external partners about what is truly beneficial in an overall business sense. “I have this great opportunity at Achaogen to build an antibody development function basically from zero,” she says. “I was mostly on the side pushing for innovations when I was at Genentech, and I can see that the equation doesn’t change that much. You have to understand what the positive impact of innovations are to the sponsor’s business.”

Her prime example is a first assumption by large molecule CMOs: Improvement in titers drives down the cost of goods. “This isn’t unlike other industries with supply chains and strong competition between service providers,” she says. “In the chemical industries, if you figure out how to get a 10 percent improvement in your distillation column, you can practically retire on that. However, a CMO’s idea to double the titer for one of my processes isn’t necessarily going to drive down the cost of my goods, and it certainly won’t induce us to make a business decision. Actually, in some situations, you could be offered 200 percent more material out of a biologics manufacturing process, but who cares? Honestly, I hate to say that, but that’s not the real target.”

So what is?

Fundamentally, throughout the entire pipeline, this business is all about speed to market. “That’s the business driver. It’s not about manufacturing,” says Larson emphatically. “It is about being the first one to get a product to market and as fast as we can. Our process is essentially locked at market application for this purpose. This is the context for that 200-percent improvement in output. Any post-filing innovation of that sort will be offset by the cost of new filings, potentially even redoing a clinical trial, and specifically our speed to market. It simply is not worth it.”

Fundamentally, throughout the entire pipeline, this business is all about speed to market. “That’s the business driver. It’s not about manufacturing,” says Larson emphatically. “It is about being the first one to get a product to market and as fast as we can. Our process is essentially locked at market application for this purpose. This is the context for that 200-percent improvement in output. Any post-filing innovation of that sort will be offset by the cost of new filings, potentially even redoing a clinical trial, and specifically our speed to market. It simply is not worth it.”

She adds that, even premarket, you need to decide if you are talking about improving a process that in any way could slow you down from getting to your filings. “If so, it’s probably not worth it. I mean, I see an underestimation of speed to market as being the key driver of this industry for most products. CDMOs, CMOs, and our own process-development folks need to take this to heart.”

Larson provides an example where a service provider was pushing for an improved titer, but that increase consequently resulted in a different quality profile and more variants; the material would end up harder to purify with less consistent production. “We’ve seen companies push levels up to multiple grams per liter, but they actually never ran that at commercial scale,” she explains. “There’s this tendency to become obsessed with cell-culture yield because it’s an easy metric. But if you lose one or two runs in manufacturing, the cost completely wipes out your titer improvement.”

“For years we’ve focused on the drug substance, but increasingly the differentiation is in other areas, for example on device and delivery,” she continues. “So you are focusing on getting your drug substance down to $10 a dose from the antibody production, but then you put that in a device that brings your dose closer to $50. You’re focusing on the wrong place. You might want to be looking at things like the likelihood of delivery by sterile, prefilled syringes, and simply the best quality and consistency from your CMO.”

Larson makes clear that sponsors like Achaogen are looking for continued modernization — implementation of up-to-date equipment and technologies — to produce material reliably and consistently. However, she says the disconnect is when CMOs bring ideas and the sponsor has to respond: “Yes, we want better titer output, and higher purification, but that’s not the key drivers of our business. We’d need more foundational innovation to make a real business difference.”

So what would a foundational innovation be? One example, says Larson, is dramatically rethinking how to work with cell lines. “Maybe it’s cell-expression systems, or something like cell-free synthesis that Jim Swartz [Stanford University’s James H. Clark professor at the School of Engineering, and professor of chemical engineering and bioengineering] has been working on for years. Others have looked at E. coli expression systems, although here the purification is still quite challenging. I think that the foremost opportunity for game-changing innovation today is basically cleaning up the expression systems, although that’s obviously not going to be easy.”

She believes that the bottom line is that high-yield manufacturing gets completely disconnected with the overall business. “Look at the wider industry today, particularly as we move to more personalized medicine, high-potency products, and advanced delivery systems, all meaning less volume,” she explains. “I have worked on products where all the material needed for a decade could be produced by just doing the qualification batches. More than ever, sponsors and their service providers have to keep an eye on the evolving business strategies and global markets. The real value is in understanding how our businesses actually operate.”

What’s A CMO To do?
That understanding starts with knowing yourself; understand what you are good at. Second, know your customers; learn their real business drivers and needs.

Consider the needs in some therapeutic areas for massive amounts of drug substance and product. For example, a customer developing drugs for Alzheimer’s disease or diabetes will potentially be dosing chronically for decades. Larson says, “There’s probably not enough manufacturing capacity in the world to make some of the needed antibodies.” The questions to ask yourself include:

• Are you a CMO geared for this type of large-scale need?
• How can you continue to modernize to serve these customers?
• Or, are you better suited for clients with ADCs (antibody-drug conjugates), with little need for antibodies?

“We have this kind of bifurcation of volume in the industry,” Larson says. “There are CMOs that recognize and are taking advantage of the opportunity by understanding precisely who they are and what services and innovation their clients need to drive their business decisions in that realm.”

In summary, Larson reiterates the need for small molecule-focused CMOs to modernize their facilities, and she again cautions that the biologicsfocused folks not get complacent. Both sides need to continue to implement the newest technologies and equipment with the goal being to achieve the best quality, consistency, and reliability, all leading to enhancing speed to market for customers.

Perhaps the best outcome will be a convergence of technology and understanding of both sides (small and large molecule). That may actually be led by the new kids on the block: the single-use or continuous-manufacturing innovators, and for example, those working on niche cell-based therapies. So who knows? Perhaps after all, innovation — the meaningful kind — will soon drive Larson and others in their business decisions. She certainly won’t be shy about letting partners know when that happens.